CN115611860A - Method for synthesizing nilapanib - Google Patents

Method for synthesizing nilapanib Download PDF

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CN115611860A
CN115611860A CN202110790292.3A CN202110790292A CN115611860A CN 115611860 A CN115611860 A CN 115611860A CN 202110790292 A CN202110790292 A CN 202110790292A CN 115611860 A CN115611860 A CN 115611860A
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formula
compound
solvent
reaction
nilapanib
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CN115611860B (en
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郭朋
赖伟全
何成涛
朱文峰
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Bopunuo Shanghai Pharmaceutical Technology Development Co ltd
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Shanghai Vastpro Technology Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The application discloses a method for synthesizing nilapanib. In the present application, the method comprises the steps of: (1) Carrying out hydrogenolysis reaction on a compound shown as a formula I-1 in a solvent in the presence of a catalyst to obtain a compound shown as a formula IV; and (2) treating the compound of formula IV with methanesulfonic acid in a solvent to obtain the nilapanib (compound of formula V). The method for synthesizing the nilapanib provided by the invention has concise steps; chiral resolution is not needed, and the yield is high; sodium azide is not needed, the safety is greatly improved, and the method is suitable for industrialization.

Description

Method for synthesizing nilapanib
Technical Field
The embodiment of the invention relates to the field of organic synthesis, in particular to a method for synthesizing nilapanib.
Background
Nilapanib (trade name zejua) is an inhibitor of poly (adenosine diphosphate ribose polymerase) (PARP) developed by Tesaro corporation, whose active ingredient is a free base and whose stabilizing ingredient is a p-toluenesulfonate salt (as shown in the following formula a) or hydrochloride salt containing one molecule of crystal water.
Figure BDA0003160607340000011
Nilapanib was approved by the FDA for marketing on 27/3/2017, and was used primarily for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, as well as for maintenance therapy in adult patients who responded in whole or in part to platinum-based chemotherapeutic drugs. The nilapanib has the advantages of wide adaptation diseases, good treatment effect and huge market demand. In the prior art, 4- (3S) -3-piperidyl-aniline is mainly used as an important intermediate for synthesizing Nilaparib, and the specific route is as follows:
Figure BDA0003160607340000012
the inventor finds that the starting materials are expensive 4-iodonitrobenzene and 3-pyridine boric acid when the nilapanib is synthesized by taking 4- (3S) -3-piperidyl-aniline as an important intermediate, and catalysts such as triphenylphosphine palladium, platinum oxide and the like are expensive, so that high cost is caused; in the second step, the hydrogenation pressure is higher, and industrialization is difficult to realize; in the resolution of the enantiomer, the qualified enantiomer can be obtained only by three times of recrystallization, and the chiral material loss is serious; sodium azide which is extremely easy to explode and used in the last step has great safety risk under the condition of higher reaction temperature; in addition, the yield of the whole synthesis route is extremely low, and the scale popularization is not facilitated.
In order to avoid using high-position sodium azide and chemical chiral resolution, the prior art also discloses a method for synthesizing nilapanib by taking (S) -3- (4-bromophenyl) -piperidine as an intermediate, and the specific route is as follows:
Figure BDA0003160607340000021
the method not only avoids using sodium azide, but also utilizes enzyme catalysis to construct the chiral center, avoids material loss in the step of chemical chiral resolution, has longer synthetic route and more steps, is difficult to obtain the enzyme for catalytically constructing the chiral center, and is difficult to popularize on a large scale.
Therefore, there is still a need to develop a method for synthesizing nilapanib with simple steps, high safety, low cost, high yield and suitable for large-scale industrialization.
Disclosure of Invention
The embodiment of the invention aims to provide a method for synthesizing nilapanib, which has the advantages of simple steps, high safety, low cost and high yield and is suitable for large-scale industrialization.
It is another object of embodiments of the present invention to provide nilapanib intermediates.
Another object of an embodiment of the present invention is to provide a process for preparing a nilapanib intermediate.
To solve the above problems, an embodiment of the present invention provides a method for synthesizing nilapanib, the method comprising the steps of:
(1) Carrying out hydrogenolysis reaction on the compound of the formula (I-1) in the presence of a catalyst to obtain a compound of a formula (IV),
Figure BDA0003160607340000031
and
(2) Treating the compound of formula (IV) with methanesulfonic acid in a solvent to obtain the nilapanib (compound of formula (V)),
Figure BDA0003160607340000032
in some preferred embodiments, in step (1), the catalyst is a palladium catalyst, for example: 20% of Pd (OH) 2 -C、Pd-C、PdCl 2 、Pd/HCOOH、Pd-C/HCOOH、Pd-C/HCOONH 4 、Pd-C/NH 2 NH 2 Pd-C/cyclohexene.
In some preferred embodiments, in step (1), the hydrogenolysis reaction is carried out in the presence of acetic acid.
In some preferred embodiments, in step (1), the solvent is C 1～4 An alcohol, more preferably methanol.
In some preferred embodiments, in step (1), the reaction temperature is 40 to 60 ℃.
In some preferred embodiments, in step (1), the hydrogenolysis reaction is terminated and then filtered through celite and the filtrate is concentrated.
In some preferred embodiments, in step (2), the solvent is an organic solvent, more preferably at least one hydrogen atom is replaced by C 1～3 Alkyl-substituted benzene, wherein, C 1～3 The alkyl is any one of methyl, ethyl, n-propyl or isopropyl; for example: ortho-xylene.
In some preferred embodiments, in step (2), the reaction temperature is 30 to 50 ℃, for example 40 ℃.
In some preferred embodiments, the nilapanib obtained in step (2) is purified by the following method: dissolving the nilapanib (compound of formula V) obtained in the step (2) in water, adding p-toluenesulfonic acid or a hydrate thereof, stirring and filtering to obtain the p-toluenesulfonic acid salt of nilapanib.
In some preferred embodiments, the p-toluenesulfonate salt of nilapanib obtained is further purified by the following method: heating and refluxing the p-toluenesulfonate of the nilapanib in a mixed solvent of acetonitrile and water, carrying out thermal filtration, evaporating the acetonitrile, cooling and filtering to obtain the purified p-toluenesulfonate of the nilapanib.
Embodiments of the present invention also provide a nilapanib intermediate a having a structure represented by formula (i-1):
Figure BDA0003160607340000041
embodiments of the present invention also provide a nilapanib intermediate B having a structure described by formula (ii-1) or formula (ii-2):
Figure BDA0003160607340000042
in the formula (II-2), X is bromine.
Embodiments of the present invention also provide a method of synthesizing nilapanib intermediate a of formula (i-1) (a compound of formula (i-1)) comprising the steps of:
in a solvent, in the presence of alkali, the compound of formula (II-1) and the compound of formula (III) are subjected to coupling reaction in the presence of a copper source catalyst to obtain the compound of formula (I-1) (namely a nilapanib intermediate A),
Figure BDA0003160607340000043
in the compound of formula (II-1), X is bromine.
In some preferred embodiments, the copper source catalyst is metallic copper or cuprous halide, and the cupric halide is preferably CuCl, cuBr, or CuI.
In some preferred embodiments, the base is an alkali metal carbonate or phosphate, more preferably K 2 CO 3 、K 3 PO 4 Or Cs 2 CO 3 。
In some preferred embodiments, the solvent is DMSO, DMAC, or DMF.
In some preferred embodiments, the coupling reaction is carried out in the presence of 8-hydroxyquinoline.
In some preferred embodiments, the compound of formula (II-1) can be prepared by:
(F) Carrying out diazotization reaction on sodium nitrite and a compound of a formula (II-2) in the presence of acid to obtain a diazonium salt of the compound of the formula (II-2), and then carrying out co-heating on the diazonium salt of the compound of the formula (II-2) with cuprous bromide and hydrobromic acid under the catalysis of cuprous halide to obtain the compound of the formula (II-1),
Figure BDA0003160607340000051
in the compound of the formula (II-1), X is bromine.
In some preferred embodiments, the diazotization reaction is carried out at a temperature of from-5 to 5 deg.C, more preferably from 0 to 4 deg.C.
In some preferred embodiments, the diazotization reaction is carried out in the presence of concentrated sulfuric acid.
In some preferred embodiments, the compound of formula (II-1) is purified by the following method: the compound of formula (II-1) was extracted with ethyl acetate, the organic phase was separated and concentrated.
In some preferred embodiments, the compound of formula (II-2) can be prepared by:
(A) Reacting (S) -phenethylamine with 1, 3-chlorobromomethane in a solvent in the presence of alkali to obtain (S) -3-chloro-N- (1-phenylethyl) propylamine,
Figure BDA0003160607340000052
(B) In a solvent, carrying out condensation reaction on the (S) -3-chloro-N- (1-phenylethyl) propylamine obtained in the step (A) and p-nitroacetophenone to obtain a compound of a formula (VII-1),
Figure BDA0003160607340000053
(C) Treating the compound of the formula (VII-1) with a reducing agent in a solvent to obtain a compound of the formula (VII-2),
Figure BDA0003160607340000061
(D) Treating the compound of the formula (VII-2) with a reducing agent in a solvent to obtain the compound of the formula (II-2),
Figure BDA0003160607340000062
in some preferred embodiments, in step (a), the base is an alkali metal carbonate, such as: potassium carbonate.
In some preferred embodiments, in step (a), the solvent is an organic solvent, such as: dimethylformamide (DMF).
In some preferred reactions, in step (A), the (S) -phenylethylamine and 1, 3-bromochloropropane are fed in an equivalent ratio of: 1:1.
In some preferred reactions, the temperature of the reaction in step (a) is in the range of 20 to 30 ℃, for example 25 ℃.
In the step (B), the condensation reaction comprises the following specific steps: and (S) -3-chloro-N- (1-phenylethyl) propylamine obtained in the step (A), p-nitroacetoacetic acid and N, N' -carbonyldiimidazole are sequentially put into a solvent in the presence of an inert gas for condensation reaction.
In some preferred embodiments, in step (B), the feed equivalent ratio of (S) -3-chloro-N- (1-phenylethyl) propylamine to p-nitrophenylacetic acid to N, N' -carbonyldiimidazole is: 1:1:2.
In some preferred embodiments, in step (B), the solvent is an organic solvent, more preferably C 1～8 Esters, such as isopropyl acetate.
In some preferred embodiments, in step (B), the inert gas is nitrogen or argon, more preferably nitrogen.
In some preferred embodiments, in step (B), the condensation reaction is carried out at a temperature of from 35 to 55 deg.C, for example 40 deg.C.
In the step (C), the compound of the formula (VII-1) is treated with a reducing agent, and-NO on the benzene ring in the molecule of the compound of the formula (VII-1) 2 Is reduced to-NH 2 Understandably, the reaction of-NO on the benzene ring, as is common in organic synthesis 2 Is reduced to-NH 2 The methods of (1) are suitable for this purpose, and non-limiting examples are: catalytic hydrogenation, ferrite reduction (heat treatment of the substance to be reduced with iron powder and hydrochloric acid in a solvent), tin chloride reduction (heat treatment of the substance to be reduced with tin chloride in a solvent), and the like, preferably, the compound of formula (VII-1) is reduced using catalytic hydrogenation, based on the advantageous effects of simple procedure and easy industrialization.
In some preferred embodiments, in step (C), the solvent is an organic solvent, more preferably C 1～4 Alcohols, such as methanol.
In some preferred embodiments, in step (C), the reducing agent is hydrogen.
In some preferred embodiments, in step (C), the treatment specifically includes the steps of: treating the compound of formula (VII-1) with hydrogen in a solvent in the presence of a catalyst.
In some preferred embodiments, in step (C), the pressure of the hydrogen is 1.2 to 2.5MPa, for example 2MPa.
In some preferred embodiments, in step (C), the catalyst is Raney nickel (Ranry nickel), pd/C or Pt/C.
In the step (D), the compound of the formula (VII-2) is treated with a reducing agent, and the amide in the molecule of the compound of the formula (VII-2) is reduced to an amine, and understandably, the method for reducing the amide to an amine which is common in organic synthesis is applicable to this, and there are mentioned, but not limited to: naBH 4 Reduction method of Lewis system, reduction method of lithium aluminum hydride, etc., preferably, naBH is used 4 Reduction of the compound of formula (VII-2) by reduction with a Lewis system.
In some preferred embodiments, in step (D), the reducing agent is NaBH 4 Said treatment being carried out in the presence of a Lewis acid.
In some preferred embodiments, in step (D), the lewis acid is boron trifluoride complex, aluminum trichloride, ferric trichloride, cobalt chloride, titanium chloride, or nickel chloride, and more preferably, the lewis acid is boron trifluoride diethyl etherate complex, boron trifluoride tetrahydrofuran complex, or aluminum trichloride.
In some preferred embodiments, in step (D), the solvent is tetrahydrofuran or dimethylsulfoxide.
In some preferred embodiments, in step (D), the treatment specifically comprises the steps of: treating the compound of formula (VII-2) with sodium borohydride in a solvent in the presence of a Lewis acid.
Compared with the prior art, the embodiment of the invention has at least the following advantages:
the nilapanib intermediate B provided by the invention is easy to obtain synthetic raw materials, is an ideal chiral source, and can be easily obtained by removing an amino protecting group from the nilapanib intermediate A obtained by the method.
The method for synthesizing the nilapanib provided by the invention has simple steps.
The method for synthesizing the nilapanib provided by the invention does not need chiral resolution, and has high yield.
The method for synthesizing the nilapanib provided by the invention does not need to use sodium azide, greatly improves the safety, and is suitable for industrialization.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the present invention is further described below with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs, and it is to be noted that the terms used herein are merely for describing particular embodiments and are not intended to limit exemplary embodiments of the present application.
EXAMPLE I preparation of the Compound of formula (VII-1)
The compound of formula (VII-1) is prepared by the process of patent CN109265390, and the specific preparation is carried out by the following steps:
firstly, (S) -phenethylamine is subjected to Hofmann alkylation reaction in the presence of alkali to obtain a product (S) -3-chloro-N- (1-phenylethyl) propylamine. The method comprises the following specific steps: 1 equivalent of (S) -phenethylamine, 1 equivalent of 1, 3-bromochloropropane, 1 equivalent of potassium carbonate and 5 volumes of dimethylformamide are added into a reaction kettle, and the mixture is stirred at room temperature (25 ℃) until the reaction end point. Adding water and ethyl acetate for extraction, washing an ethyl acetate layer with water, concentrating to obtain (S) -3-chloro-N- (1-phenylethyl) propylamine, using hydrogen chloride to form hydrochloride, and filtering and separating to obtain a solid, namely the hydrochloride of the (S) -3-chloro-N- (1-phenylethyl) propylamine.
Figure BDA0003160607340000081
Secondly, the (S) -3-chlorine-N- (1-phenylethyl) propylamine and the p-nitrophenylacetic acid are subjected to condensation reaction in the presence of N, N' -carbonyldiimidazole to obtain the product, namely the compound shown in the formula (VII-1). The method comprises the following specific steps: sequentially adding 1 equivalent of (S) -3-chloro-N- (1-phenylethyl) propylamine, 1 equivalent of p-nitrophenylacetic acid and 10 equivalents of isopropyl acetate into a reaction kettle, heating to 40 ℃ under the protection of nitrogen, adding 2 equivalents of N, N' -carbonyldiimidazole in batches, and stirring at the temperature of 40 ℃ until the reaction end point. After the reaction, the mixture was cooled to 20 ℃, the pH =3 to 4 was adjusted with hydrochloric acid, the mixture was washed with stirring to separate layers, and the organic layer was washed once with a saturated sodium bicarbonate solution and water. The organic layer was concentrated to dryness under reduced pressure and then dissolved with 10 volumes of acetonitrile. Adding 2 equivalents of anhydrous potassium carbonate and 0.1 equivalent of 18-crown-6, heating to 50 ℃, and stirring while keeping the temperature until the reaction is finished. Cooling to 20 deg.C, filtering to remove inorganic salts, adjusting pH of the filtrate to 5 with hydrochloric acid, and concentrating to dryness. Adding dichloromethane and water, stirring and layering to obtain an organic layer, concentrating the organic layer under reduced pressure until the organic layer is dried, adding 2 volumes of MTBE (methyl tert-butyl ether) into the concentrate, heating to reflux, slowly cooling to-5-0 ℃, performing suction filtration, leaching a filter cake with MTBE (methyl tert-butyl ether), and performing vacuum drying on the filter cake to obtain the compound of the formula (VII-1), wherein the yield is about 56%.
Figure BDA0003160607340000091
EXAMPLE two preparation of the Compound of formula (VII-2)
And (3) reducing the compound of the formula (VII-1) by using a catalytic hydrogenation method to obtain a product compound of the formula (VII-2). The method comprises the following specific steps: 200g of the compound (VII-1) (d.e. = 98%), 1000mL of methanol, 20g of Raney nickel and 60g of sulfuric acid are put into a reaction bottle, and the mixture is stirred and reacted at the external temperature of 40-60 ℃ under the hydrogen pressure of 2MPa until the raw materials are completely converted. The catalyst is removed by diatomite filtration, and the filtrate is concentrated to obtain the compound shown in the formula (VII-2), which is directly used for the next reaction without other treatment. The yield thereof was found to be 100%.
Figure BDA0003160607340000092
In the third example, acetic acid was used instead of sulfuric acid in the second step of the example, and the rest of the procedure was the same. The method comprises the following specific steps: 200g of the compound (VII-1) (d.e. = 98%), 1000mL of methanol, 20g of Raney nickel and 55g of acetic acid are put into a reaction bottle, and the mixture is stirred and reacted at an external temperature of 40-60 ℃ under a hydrogen pressure of 2MPa until the conversion of the raw materials is complete. The catalyst is removed by filtering through diatomite, and the filtrate is concentrated to obtain the compound shown as the formula (VII-2), which directly enters the next reaction without other treatment. The yield thereof was found to be 100%.
EXAMPLE four preparation of Compound of formula (II-2)
The compound of the formula (VII-2) is reduced by using a NaBH4-Lewis system reduction method, namely, the compound of the formula (VII-2) is reduced by using NaBH4 as a reducing agent in the presence of Lewis acid to obtain a product, namely the compound of the formula (II-2). The method comprises the following specific steps: 70g of sodium borohydride and 500mL of tetrahydrofuran are put into a reaction bottle, and the temperature is reduced to 0 ℃. 181.g of the compound of the formula (VII-2) was added. While the internal temperature was kept at 10 ℃ or less, 320g of boron trifluoride etherate in 500mL of tetrahydrofuran was added dropwise. After the dripping is finished, slowly raising the temperature to room temperature, and stirring until the reaction is complete. While maintaining the temperature at 25 ℃ or below, 400mL of water and 400mL of hydrochloric acid are added dropwise. After the dripping is finished, the temperature is raised to 50 ℃, and the mixture is stirred until the reaction is complete. After cooling to 0 ℃, the pH is adjusted to above 12 with alkaline water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined and washed with water. The organic phase is concentrated to give the compound of formula (II-2).
Figure BDA0003160607340000101
Taking a small amount of crude product for column chromatography purification and then carrying out nuclear magnetic structural characterization. 1 H NMR(CDCl 3 ,400MHz):δ＝7.33-7.26(m,4H),7.25-7.16(m,1H),6.96(d,J＝8.4Hz,2H),6.59(d,J＝8.4Hz,2H),3.52(q,J＝6.8Hz,1H),3.02(d,J＝11.2Hz,1H),2.92(d,J＝11.2Hz,1H),2.72-2.58(m,1H),1.96(dt,J＝11.2,3.6Hz,1H),1.92-1.80(m,2H),1.80-1.70(m,2H),1.39(d,J＝6.8Hz,3H),1.32ppm(dd,J＝12.0,4.8Hz,1H)。
In example five, boron trifluoride tetrahydrofuran complex was used instead of boron trifluoride diethyl etherate complex in the fourth step of example, and the rest of the procedure was the same. The method comprises the following specific steps: 70g of sodium borohydride and 500mL of tetrahydrofuran are put into a reaction bottle, and the temperature is reduced to 0 ℃. 181.g of the compound of the formula (VII-2) was added. An inner temperature was controlled not to exceed 10 ℃ and a solution of 345g of boron trifluoride tetrahydrofuran complex in 500mL of tetrahydrofuran was added dropwise. After the dripping is finished, slowly raising the temperature to room temperature and stirring the mixture until the reaction is complete. The temperature is maintained to be not more than 25 ℃, and 400mL of water and 400mL of hydrochloric acid are added dropwise. After the dripping is finished, the temperature is raised to 50 ℃, and the mixture is stirred until the reaction is complete. After cooling to 0 ℃, the pH is adjusted to above 12 with alkaline water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined and washed with water. The organic phase is concentrated to give the compound of formula (II-2).
In the sixth example, aluminum trichloride was used instead of boron trifluoride etherate in the fourth step, and the rest of the procedure was the same. The method comprises the following specific steps: 70g of sodium borohydride and 500mL of tetrahydrofuran are put into a reaction bottle, and the temperature is reduced to 0 ℃. 181.g of the compound of the formula (VII-2) was added. An internal temperature was controlled not to exceed 10 ℃ and a solution of 222g of aluminum trichloride in 500mL of tetrahydrofuran was added dropwise. After the dripping is finished, slowly raising the temperature to room temperature, and stirring until the reaction is complete. While maintaining the temperature at 25 ℃ or below, 400mL of water and 400mL of hydrochloric acid are added dropwise. After the dripping is finished, the temperature is raised to 50 ℃, and the mixture is stirred until the reaction is complete. After cooling to 0 ℃, the pH is adjusted to above 12 with alkaline water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined and washed with water. The organic phase is concentrated to give the compound of formula (II-2).
EXAMPLE seven preparation of the Compound of formula (II-1)
The diazo salt of the compound of formula (II-2) is used to be co-heated with hydrobromic acid to obtain the product compound of formula (II-1). The method comprises the following specific steps: firstly, diazotization reaction is carried out on the compound of the formula (II-2) to obtain the product, namely the diazonium salt of the compound of the formula (II-2). The method comprises the following specific steps: adding 60mL of water and 35g of concentrated sulfuric acid (with the mass percentage content of 98-99 percent and chemical purity) into a reaction bottle, uniformly mixing, adding 20g of a compound III, and cooling to-5 ℃. While maintaining this temperature, 6g of an aqueous solution of sodium nitrite was added dropwise. After the addition, the mixture is stirred for 1 hour to obtain the diazonium salt of the compound shown in the formula (II-2). Then, 40mL of hydrobromic acid, 10g of cuprous bromide and 200mL of acetone were added to another reaction flask. After heating to 60 ℃, the diazonium salt solution of the compound of formula (II-2) prepared previously is added dropwise. After the dripping is finished, stirring the mixture until the reaction is complete. The reaction solution was extracted with ethyl acetate 2 times, and after organic phases were combined, the mixture was washed with a sodium carbonate solution and water in this order. The organic phase is concentrated to give the compound of formula (II-1). The yield thereof was found to be 95%. The reaction mixture was used in the next reaction without further purification.
Figure BDA0003160607340000111
Taking a small amount of crude product for column chromatography purification and then carrying out nuclear magnetic structure characterization. 1 H NMR(DMSO-d 6 ,400MHz):δ＝7.43(d,J＝8.4Hz,2H),7.34-7.27(m,4H),7.25-7.17(m,1H),7.14(d,J＝8.4Hz,2H),3.50(q,J＝6.8Hz,1H),2.95(d,J＝11.2Hz,1H),2.77(d,J＝10.4Hz,1H),2.72-2.62(m,1H),1.95(dt,J＝11.6,2.8Hz,1H),1.89(t,J＝10.8Hz,1H),1.80-1.67(m,2H),1.65-1.52(m,1H),1.40-1.32(m,1H),1.31ppm(d,J＝6.8Hz,3H)。
EXAMPLE eight preparation of the Compound of formula (I-1)
And (3) carrying out Ullmann C-N coupling reaction on the compound of the formula (II-1) to obtain a product compound of the formula (I-1). The method comprises the following specific steps: a reaction flask was charged with 20g of the compound of formula (II-1), 13g of N-tert-butyl-1H-indazole-7-carboxamide, 18g of potassium carbonate, 0.5g of cuprous bromide, 1.7g of 8-hydroxyquinoline, and 200mL of dimethylacetamide. Heating to 120-140 deg.c and stirring to complete reaction. After cooling to room temperature, 500mL of water was added dropwise and filtered to give 25g of a light-colored solid as the compound of formula (I-1) in 89% yield. Used in the next reaction without purification.
Figure BDA0003160607340000112
Taking a small amount of crude product for column chromatography purificationAnd then carrying out nuclear magnetic structural characterization. 1 H NMR(CDCl 3 ,400MHz):δ＝9.32(s,1H),8.46(s,1H),8.25(d,J＝7.2Hz,1H),7.82(d,J＝7.2Hz,1H),7.77(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),7.33-7.30(m,4H),7.26(m,2H),3.55(q,J＝6.8Hz,1H),3.08(d,J＝11.2Hz,1H),2.99(d,J＝11.2Hz,1H),2.86(tt,J＝11.2,3.6Hz,1H),2.10-1.98(m,2H),1.98-1.90(m,1H),1.85-1.72(m,2H),1.58(s,9H),1.50-1.42(m,1H),1.42ppm(d,J＝6.8Hz,3H)。
In example nine, cuprous iodide was used instead of cuprous bromide in the example eight step, and the remaining steps were the same. The method comprises the following specific steps: a reaction flask was charged with 20g of the compound of formula (II-1), 13g of N-tert-butyl-1H-indazole-7-carboxamide, 20g of potassium carbonate, 2g of cuprous iodide, 1.7g of 8-hydroxyquinoline and 200mL of dimethylacetamide. Heating to 120-140 deg.c and stirring to complete reaction. After cooling to room temperature, 500mL of water was added dropwise and filtered to give 25g of a light-colored solid as the compound of formula (I-1) in 89% yield. Used in the next reaction without purification.
In example ten, dimethyl sulfoxide was used instead of dimethylacetamide in the step of example eight, and the remaining steps were the same. The method comprises the following specific steps: a reaction flask was charged with 20g of the compound of formula (II-1), 13g of N-tert-butyl-1H-indazole-7-carboxamide, 22g of tripotassium phosphate, 1g of cuprous bromide, 1.7g of 8-hydroxyquinoline, and 200mL of dimethyl sulfoxide. Heating to 120-140 deg.c and stirring to complete reaction. After cooling to room temperature, 500mL of water was added dropwise and filtered to give 25g of a light-colored solid as the compound of formula (I-1) in 89% yield. Used in the next reaction without purification.
EXAMPLE eleventh preparation of Nilaparib
The preparation of nilapanib was carried out by the following steps:
firstly, the compound of formula (I-1) is catalyzed and hydrogenolyzed to remove benzyl to obtain a product of formula (IV). The method comprises the following specific steps: a hydrogenation reaction flask was charged with 18g of the compound of formula (I-1), 1.8g of palladium hydroxide on carbon, 20mL of acetic acid, and 200mL of methanol. Stirring the mixture at 40 to 60 ℃ under the pressure of 20Kg of hydrogen until the reaction is complete. A little amount of diatomite is filtered to remove the catalyst, and the filtrate is concentrated to be dry to obtain the crude product of the compound shown in the formula (IV).
Figure BDA0003160607340000121
Secondly, the compound of the formula (IV) is removed with tert-butyl to obtain the product of Nilaparib. The method comprises the following specific steps: 40mL of o-xylene and 60mL of methanesulfonic acid were added to Compound VI. Stirring at 40 ℃ until the reaction is complete. After cooling to room temperature, 140mL of water was added dropwise. The layers were separated and the aqueous phase was washed 2 times with toluene to give nilapanib (compound of formula (v)).
Figure BDA0003160607340000122
EXAMPLE eleventh preparation of Nilaparib p-toluenesulfonate salt
To the aqueous phase obtained in the reaction of example ten, 20mL of an aqueous solution of 11g of p-toluenesulfonic acid monohydrate was added dropwise with stirring at room temperature. After dropping, stir at room temperature overnight. Filtering and drying to obtain a crude product. Acetonitrile 200mL and water 200mL are added to the crude product and the mixture is warmed to reflux. After filtration, the filtrate is decompressed and evaporated to remove acetonitrile, the remainder is slowly cooled to room temperature, and white-like solid, namely the nilapanib p-toluenesulfonate, is obtained by filtration. Example ten and example eleven two-step overall yield 80%, ee% =99.8%.
And taking a small amount of product for column chromatography purification and then carrying out nuclear magnetic structural characterization. 1 H NMR(CD 3 OD,400MHz):δ＝8.99(s,1H),8.17(dd,J＝7.2,1.2Hz,1H),8.10-8.03(m,2H),8.02(dd,J＝8.4,1.2Hz,1H),7.76-7.68(m,2H),7.56-7.48(m,2H),7.27(dd,J＝8.4,6.8Hz,1H),7.23(d,J＝8.0Hz，2H),3.55-3.42(m，2H),3.22-3.02(m,3H),2.35(s,3H),2.15-2.05(m,2H),2.00-1.80ppm(m,2H)。
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples for carrying out the invention, and that various changes in form and details may be made therein without departing from the spirit and scope of the invention in practice.

Claims (10)

1. A method of synthesizing nilapanib comprising the steps of:
(1) In a solvent, carrying out hydrogenolysis reaction on a compound shown as a formula I-1 in the presence of a catalyst to obtain a compound shown as a formula IV,
Figure FDA0003160607330000011
and
(2) Treating the compound shown in the formula IV with methanesulfonic acid in a solvent to obtain the nilapanib (the compound shown in the formula V),
Figure FDA0003160607330000012
2. the process of claim 1, wherein the compound of formula i-1 is prepared by: in the presence of alkali, carrying out coupling reaction on a compound shown in a formula II-1 and a compound shown in a formula III in the presence of a copper source catalyst to obtain the compound shown in the formula I-1,
Figure FDA0003160607330000013
wherein X is bromine.
3. The method of claim 2, wherein the ii-2 compound is prepared by: carrying out diazotization reaction on sodium nitrite and a compound of a formula (II-2) in the presence of acid to obtain a diazonium salt of the compound of the formula (II-2), and then carrying out co-heating on the diazonium salt of the compound of the formula (II-2) and hydrobromic acid corresponding to cuprous bromide under the catalysis of cuprous bromide to obtain the compound of the formula (II-1),
Figure FDA0003160607330000021
in the compound of formula II-1, X is bromine.
4. The method of claim 3, wherein the compound of formula ii-2 is prepared by:
(C) Treating the compound of the formula VII-1 with a reducing agent in a solvent to obtain a compound of the formula VII-2,
Figure FDA0003160607330000022
(D) Treating a compound of formula VII-2 with a reducing agent in a solvent to obtain said compound of formula II-2,
Figure FDA0003160607330000023
5. the process according to any one of claims 1 to 4, wherein in step (1), the catalyst is a palladium catalyst;
and/or, in step (1), the hydrogenolysis reaction is carried out in the presence of acetic acid;
and/or, in the step (1), the solvent is C 1～4 An alcohol;
and/or, in the step (2), the solvent is an organic solvent;
and/or in the step (2), the reaction temperature is 30-50 ℃.
6. The method of claim 2, wherein the copper source catalyst is a metallic copper or a copper halide;
and/or, the base is an alkali metal carbonate or phosphate;
and/or the solvent is DMSO, DMAC or DMF;
and/or, the coupling reaction is carried out in the presence of 8-hydroxyquinoline.
7. The method of claim 3 or 4,
and/or the diazotization reaction is carried out at the temperature of-5 ℃;
and/or the diazotization reaction is carried out in the presence of concentrated sulfuric acid;
and/or, purifying the compound of formula (II-1) by the following method: the compound of formula (II-1) was extracted with ethyl acetate, the organic phase was separated and concentrated.
8. The method of claim 4,
and/or, in step (C), the solvent is C 1～4 An alcohol;
and/or, in step (C), the reducing agent is hydrogen;
and/or, in step (D), the reducing agent is NaBH 4 Said treatment being carried out in the presence of a Lewis acid;
and/or, in step (D), the solvent is tetrahydrofuran or dimethyl sulfoxide.
9. The method according to claim 8, wherein in step (C), the processing specifically comprises the steps of: treating the compound of formula (VII-1) with hydrogen in a solvent in the presence of a catalyst;
and/or, in the step (D), the processing specifically includes the steps of: treating the compound of formula (VII-2) with sodium borohydride in a solvent in the presence of a Lewis acid.
10. A nilapanib intermediate having any one of the following structures:
Figure FDA0003160607330000031
a formula II-2; in the compound of formula II-2, X is bromine.
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